MIF is a pleiotropic cytokine involved in tumor cell proliferation, angiogenesis, and inflammation. oxMIF is the pathogenic isoform found in tumor and its stroma. Imalumab is a novel recombinant, fully human, monoclonal antibody that targets oxMIF, with antitumor activity.
Dose escalation study (3 + 3 design). Primary endpoint was maximum tolerated dose (MTD). Secondary endpoints were antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (PD). Patients (pts), previously treated with other agents, received intravenous (IV) imalumab [28-d cycles; 2 dose schedules]: biweekly in all solid tumors (Q2W); weekly in metastatic colorectal cancer (mCRC), metastatic ovarian cancer (OvCa), and metastatic non-small cell lung cancer (NSCLC) (QW).
50 pts dosed on the trial: 19 (Q2W) in 6 cohorts (1, 3, 10, 25, 37.5, and 50 mg/kg), and 31 (QW) in 2 cohorts (10 and 25 mg/kg) including expansion (10 mg/kg) into mCRC, OvCa, and NSCLC. Dose escalation was stopped at 50 mg/kg (Q2W) and 25 mg/kg (QW). MTD was not reached. One mCRC pt reported dose-limiting toxicities: hypersensitivity pneumonitis (Q2W; 50 mg/kg) at grade 3. One NSCLC pt had grade 3 treatment-related AEs (TRAE): constipation, nausea, and vomiting. Grade 2 TRAEs included: fatigue (n = 2), diarrhea (n = 1), peripheral edema (n = 1), infusion reaction (n = 1), and urticaria (n = 1). Stable disease (SD) ≥4 mo was seen in 8 pts, including 1 pt with NSCLC who achieved SD for 12.6 mo and 1 with OvCa ongoing beyond 10 mo. In DS2, pre- and on-therapy tumor biopsies showed tissue penetration of imalumab resulting in target saturation in all biopsy-evaluable patients in all 3 tumor types. Biopsies revealed regulation of PI3K-AKT-mTOR downstream signaling, TNF-α signaling, anti-inflammatory cytokines (IL-1 and IL-10), and apoptosis. Based on clinical PK and PD study, 10 mg/kg weekly was considered a biologically active dose and sufficient to reach ≥95% target binding by the end of first cycle.
Imalumab 10 mg/kg IV weekly was well tolerated and showed single-agent antitumor activity in these pts.
Clinical trial identification
Legal entity responsible for the study
D. Mahalingam: Participated in Ad Boards: Baxter, Genspera, Dendreon, Sanofi, Celgene. X. Liu, S. Yazji, M. Yoon, G.Ç. Manzur, D. Adib: Employee of Baxalta. R. Kerschbaumer: Employee of Celgene A. Tsimberidou: Grants/Research Support Recipient: Onyx, EMD Serono, Baxter, Foundation Medicine All other authors have declared no conflicts of interest.